Our recent studies show that, in contrast to laboratory mice, significant numbers of anti-donor alloreactive memory T cells can be detected in cynomolgus monkeys prior to transplantation. These memory T cells are resistant to many conventional immunosuppressive drugs and to costimulation blockade by antibody treatments. It is likely that these cells can rapidly destroy donor cells after bone marrow transplantation thereby preventing the induction/maintenance of chimerism. This is strongly supported by the demonstration that mice that have been adoptively transferred with allospecific memory but not naive T cells can no longer be rendered tolerant to allotransplants via mixed chimerism or costimulation blockade. Based upon these observations, we hypothesize that the presence of allospecific memory T cells in primates prior to transplantation hinders their successful tolerization to allogeneic transplants. To test this hypothesis, we propose two specific aims: Specific aim 1. Characterize the alloreactive memory T cells present in cynomolgus pre-transplantation Specific aim 2. Evaluate the influence of alloreactive memory T cells on tolerance to and rejection of allogeneic heart and lung transplants. Our preliminary results indicate that, prior to transplantation, the level of alloreactive T cell memory varies dramatically upon the nature of the donor/recipient combination. Here, we will perform heart and lung transplants in donor/recipient combinations with either high or low memory alloreactivity and compare: the alloresponse, the rejection of allografts (acute and chronic), the ability of bone marrow transplant to induce stable mixed chimerism, the tolerogenicty of mixed chimerism and costimulation blockade protocols If successful, this research should significantly expand the successful application of tolerance protocols in heart and lung transplantation.